Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2

Abstract

. Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol 291: L1159 -L1168, 2006. First published August 4, 2006 doi:10.1152/ajplung.00168.2006-From a mouse model of hypoxiainduced pulmonary hypertension, we previously found a highly upregulated protein in the lung that we named hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1), and resistin-like molecule ␣ (RELM␣). However, the mechanisms of HIMF in the pulmonary vascular remodeling remain unknown. We now demonstrate that HIMF promoted cell proliferation, migration, and the production of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pulmonary endothelial cells as well as the production of reactive oxygen species in murine monocyte/macrophage cells. HIMF-induced CD31-positive cell infiltrate in in vivo Matrigel plugs was significantly suppressed by VEGF receptor-2 (VEGFR2) blockade. In ex vivo studies, HIMF stimulated the production of VEGF, MCP-1, and stromal cell-derived factor-1 (SDF-1) in the lung resident cells, and VEGFR2 neutralization significantly suppressed HIMF-induced MCP-1 and SDF-1 production. Furthermore, intravenous injection of HIMF showed marked increase of CD68-positive inflammatory cells in the lungs, and these events were attenuated by VEGFR2 neutralization. Intravenous injection of HIMF also downregulated the expression of VEGFR2 in the lung. These results suggest that HIMF plays critical roles in pulmonary inflammation as well as angiogenesis. vascular endothelial growth factor; monocyte chemotactic protein-1; vascular endothelial growth factor receptor-2; pulmonary inflammation; hypoxia-induced mitogenic factor; found in inflammatory zone 1; resistin-like molecule ␣ PULMONARY HYPERTENSION (PH) is a serious disease of poorly understood etiology characterized by raised pulmonary artery pressure, leading to progressive right-sided heart failure and ultimately death (32). PH results from intimal thickening of small pulmonary resistance arteries that results, at least in part, from endothelial and smooth muscle cell dysfunction and proliferation (41). Increased vascular endothelial cell (EC) proliferation and muscularization of the vasculature are the pathological characteristics of pulmonary vascular remodeling, and it has been demonstrated that this process is associated with hypoxia-induced production of angiogenic factors, inflammatory mediators, and vasoconstrictors.From a mouse model of hypoxia-induced PH, we previously found a highly upregulated protein that we named hypoxiainduced mitogenic factor (HIMF) (37). A microarray study showed that HIMF gene was significantly upregulated in the lungs of mice that were exposed to hypoxia for 1-4 days. We demonstrated that the recombinant protein of this gene has mitogenic actions and stimulated pulmonary microvascular smooth muscle cell proliferation via an Akt-dependent pathway.

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

“…Plexiform lesions can be duplicated in animal models only by VEGF receptor 2 inhibition. Interestingly, we have also shown that intravenous injection of recombinant HIMF into a mouse reduces VEGF receptor 2 expression in the lung (22). In our current study, we observed strong RELM-b immunostaining in the plexiform lesions of the scleroderma lung tissue samples, as well as of some of the idiopathic pulmonary hypertension tissue.…”

“…In this study, we show that RELM-b is expressed in the pulmonary vascular smooth muscle cells of patients with scleroderma-associated pulmonary hypertension, and that the addition of rhRELM-b to primary cultured HPASMCs induces cellular proliferation as well as activation of the ERK1/2 pathway. The concentration of rhRELM-b used for the current study was similar to what was used to demonstrate HIMF-induced smooth muscle cell proliferation (15), as well as endothelial cell proliferation (22), in our animal studies. In human aortic smooth muscle cells, Calabro and colleagues (34) found that a dose of 10-100 ng/ml rhResistin was able is elicit a promitogenic response.…”

“…Patients with pulmonary hypertension have elevated serum VEGF and high levels of VEGF mRNA and protein in the plexiform lesion itself. We previously demonstrated that HIMF causes endothelial proliferation and tubule formation, both in culture and in in vivo mouse lung (15,22). We also have shown that, in microvascular endothelial cells and in murine lung organ culture, the addition of recombinant HIMF induces VEGF expression (22).…”

“…We previously demonstrated that HIMF causes endothelial proliferation and tubule formation, both in culture and in in vivo mouse lung (15,22). We also have shown that, in microvascular endothelial cells and in murine lung organ culture, the addition of recombinant HIMF induces VEGF expression (22). Plexiform lesions can be duplicated in animal models only by VEGF receptor 2 inhibition.…”

“…We reported previously that HIMF expression is increased in the lungs of chronically hypoxic mice (15) and in the normal developing murine lung (21). We have also shown that HIMF introduced into murine lung induces angiogenesis and vascular thickening (22). Others have demonstrated that HIMF expression is increased in ovalbumin-induced asthma (19), bleomycininduced pulmonary fibrosis (23,24), compensatory growth after pneumonectomy (25), and endotoxin-induced acute lung injury (26).…”